中美仿制药研发申报流程课件

中美仿制药研发和申报流程涂家生，Ph.D.中国药科大学药剂学教授Telmail:jiashengtu@2011.11郑州中美仿制药研发和申报流程涂家生，Ph.D.我国仿制药申报、审评和研发对策主要内容中美关于原研药和仿制药的背景美国仿制药：申报、基于问题的审评和研发对策展望1234我国仿制药申报、审评和研发对策主要内容中美关于原研药和仿制药药物经济学催生美国仿制药制度美国社会安全制度导致政府赤字严重SSA已经破产：如何破局？降低医疗费用成为必然Hatch-Waxman法案出台美国FDA药品注册申请：新药（两类）、仿制药和非处方药申请药物经济学催生美国仿制药制度美国社会安全制度导致政府赤字严重1984年后NewDrugApplications(NDAs)AbbreviatedNewDrugApplications(ANDAs)

“FullReports”ofSafetyandEfficacyInvestigationsApplicanthasrightofreferencetoessentialinvestigations?

DuplicateofanalreadyapprovedproductNosafety/efficacydatapermitted(onlybioequivalence)YESNO505(b)(1)505(b)(2)505(j)1984年后NewDrugApplicationsAbbNDA的研发和申报NDA的研发和申报505(b)(1)新药申报资料内容IndexSummaryChemistry,ManufacturingandControlSamples,MethodsValidationPackageandLabelingNonclinicalPharmacologyandToxicology505(b)(1)新药申报资料内容Index6.

HumanPharmacokineticsandBioavailability7.Microbiology(foranti-microbialdrugsonly)8.ClinicalData9.SafetyUpdatereport(typicallysubmitted120daysaftertheNDA’ssubmission)6.HumanPharmacokineticsand10.Statistical11.CaseReportTabulations12.CaseReportForms13.PatentInformation14.PatentCertification10.Statistical505(b)(2):历史过程HatchWaxman法案：1984ParkmanLetterPhantomANDAFDADraftGuidanceforIndustry(1999)FDAResponsetoCitizen’sPetition(2003)可以降低研发的费用和审评力量的浪费505(b)(2):历史过程HatchWaxman法案505(b)(2)的关键:可靠性Whatis“Reliance”Bywhom?Onwhat?RelianceandExclusivityMarketvs.DataExclusivitySafety/EfficacyDatavs.CM&CdataFDAProcessforDeterminingRelianceWho,whenandhow?505(b)(2)的关键:可靠性Whatis“Reli505(b)(2)的意义介于全创新药物和仿制药之间具有专利保护，且不存在产权纠纷和仿制药不同，无替换的要求

应有突破505(b)(2)的意义介于全创新药物和仿制药之间505(b)(2)范围NewChemicalEntity(rarely)：我国1.1-1.3Newdosageform：我国5类Newdosingregimen：我国补充申请Newstrength：我国补充申请Newrouteofadministration：我国2类Newindication：我国1.6505(b)(2)范围NewChemicalEntity505(b)(2)情形Newactiveingredient(differentsalt,ester,complex,chelate,clathrate,racemate,orenantiomerofactivemoiety)NewinactiveingredientthatrequiresmorethanlimitedconfirmatorystudiesRxOTCswitchNewCombinationProducts“Genericbiologics”505(b)(2)情形Newactiveingredie505(b)(2)排他性Exclusivitiesavailablefor505(b)(2)productsNCEExclusivity(5years)NewProductExclusivity(3years)OrphanDrugExclusivity(7years)Pediatricexclusivityextensions(6months)PatentIssues505(b)(2)drugscanhaveOrangeBook-listedpatents,andenjoy30-monthstayprotectionagainstgenericcompetitorsBut,505(b)(2)NDAsmayalsobeblockedbypatentsonReferenceDrugs505(b)(2)排他性Exclusivitiesavai505(b)(2)新药的成功例子NCEThalomid®(thalidomide)(1998)MarketedunapproveddrugsLevothyroxine(2000)Guaifenesinextendedrelease(2002)Quininesulfate(2005)NewDosageFormTramadolorallydisintegratingtablets(2005)Ondansetronoralspray(filed2006)505(b)(2)新药的成功例子NCE505(b)(2)新药的例子NewDosingRegimenTramadolextendedreleasetablets(2005)NewStrength/FormulationAntara(micronizedfenofibratecaps)(2004)(130mgisBEtoTricor200mg)NewFormulation/InactiveIngredientAvita(tretinoingel)(newemollient)(1998)Abraxane(cremaphor-freepaclitaxel)(2005)Oxy-ADF(oxycodoneformulatedtoreducedrugabuse)(indevelopment)505(b)(2)新药的例子NewDosingRegim505(b)(2)新药的例子NewActiveIngredientPexeva(paroxetinemesylate)(newsalt)(2003)NewRouteofAdministrationEmezine(prochlorperazine)(newbuccal/transmucosaldelivery)(NDApending)Oralamphotericin-B(pre-clinical)RxOTCSwitchAlavert(loratadine)(2002)505(b)(2)新药的例子NewActiveIngre505(b)(2)新药的例子“GenericBiologics”Omnitrope(rHGH)(2006)Glucagen(glucagonrecombinant)(1998)Hyaluronidase(variousapprovals2004-05)Fortical(calcitoninsalmonrecombinant)(2005)*Examplesbasedonpubliclyavailableinformation505(b)(2)新药的例子“GenericBiologiFDANDA审评过程FDANDA审评过程FDA可以使用已有数据用于审评NDA吗？Hatch-Waxman之前,国会限制FDA在审评NDAX时应用NDAY的数据：“NodatainanNDAcanbeutilizedtosupportanotherNDAwithoutexpresspermissionoftheoriginalNDAholder.”[FDA“FinkelMemorandum”(1978,1981)]Hatch-Waxman解除只适合ANDAs：ANDAprocessallows“genericproducerofthefullytesteddrugtorelyonthesafetyandefficacydataofapriorapplicant....”505(b)(2)doesnotauthorizesuchdatarelianceMerelysetsconditionsforcertainNDAsRequires“fullreportsofinvestigations”establishingsafetyandeffectiveness[21USC§§355(b)(1)(A),(d)(1)]FDA可以使用已有数据用于审评NDA吗？Hatch-Wax美国仿制药

Agenericdrugproductisonethatiscomparabletoaninnovatordrugproduct(alsoknownasthereferencelisteddrug(RLD)productasidentifiedintheFDA’slistofApprovedDrugProductswithTherapeuticEquivalenceEvaluations)indosageform,strength,routeofadministration,quality,performancecharacteristicsandintendeduse.美国仿制药Agenericdrugproduct

Genericdrugapplicationsaretermed“abbreviated”inthattheyaregenerallynotrequiredtoincludepreclinical(animal)andclinical(human)datatoestablishsafetyandeffectiveness.Theseparameterswereestablishedupontheapprovaloftheinnovatordrugproduct,whichisthefirstversionofthedrugproductapprovedbytheFDA.GenericdrugapplicationsaFDA审评仿制药程序FDA审评仿制药程序二、美国仿制药的申报、审评和研发对策由FDA的OGD审评审评方式采用QbR申报资料采用CTD资料内容也针对问题二、美国仿制药的申报、审评和研发对策由FDA的OGD审评中美仿制药研发申报流程课件中美仿制药研发申报流程课件中美仿制药研发申报流程课件OfficeofGenericDrugsOfficeofGenericDrugs如何保证审评质量和效率？StructuredProductLabeling(SPL)MakeslabelingavailableonInternetviaNationalLibraryofMedicine(NLM)ReviewEfficienciesEarlyDMFreviewClusterreviews–productspecialistsSupplementtriagingatteamleaderlevelDBETruncatedReviewQuestionbasedReview(QbR)Willhaveaverypositiveimpact如何保证审评质量和效率？StructuredProductNewresourcesdevelopedDissolutionDatabaseIndividualProductBioequivalenceInformationEncouragedtheuseoftelephoneinreviewprocessIncreasedthenumberof1stcycleapprovalsDecreasedthetotalnumberofreviewcyclesTotaltimetoapprovaldidnotincreaseinspiteofincreasedworkloadNewresourcesdevelopedDissolutionMethodsforDrugProductsNew!!DissolutionMethodsforDrugPbenben中美仿制药研发申报流程课件ThisguidancecontainsanInternetlink

toalistingofdrugproducts,eachlinkedinturntoacorrespondingbioequivalencerecommendation.Clickingonaproductnameinthatlistwillbringupthebioequivalencerecommendationsforthatspecificproduct.Recommendationshavebeendevelopedforseveraldrugsthatarenotyeteligibleforgenericcompetition(i.e.,newlyapprovedproducts)andsomeolderproductsforwhichinformationhaspreviouslybeenprovided.Asadditionalrecommendationsaredeveloped,thosewillbepostedontheWebsite.Whenthisguidanceisfinalized,thelistingwillbeavailablethroughtheAgency’sWebpage.中美仿制药研发申报流程课件OFFICEOFGENERICDRUGSTABLEOFBIOEQUIVALENCERECOMMENDATIONSActiveIngredientPotencyDosageFormRouteofAdministrationDateFinalizedAlmotriptanMalate12.5mgTabletOral5/16/2005Alosetron1mgTabletOral5/31/2005Atazanavir200mgCapsuleOral3/18/2005Atomoxetine60mgCapsuleOral6/13/2005CefditorenPivoxil200mgTabletOral3/18/2005Dutasteride0.5mgCapsuleOral7/5/2005Eplerenone50mgTabletOral3/18/2005FosamprenavirCalcium700mgTabletOral3/18/2005Memantine10mgTabletOral7/8/2005Rosuvastatin40mgTabletOral3/18/2005Tadalafil20mgTabletOral3/18/2005VardenafilHCl20mgTabletOral4/11/2005OFFICEOFGENERICDRUGSTABLEOQbR:从提出到完善1/2005–2/2005:Question-basedReviewDrafted3/2005–4/2005:DivisionDirectorsDiscussion5/2005–6/2005:TeamLeadersDiscussion7/2005–8/2005:ReviewersDiscussion9/2005–1/2006:ModelPharmaceuticalDevelopmentReportandQualityOverallSummary2/2005–12/2005:DiscussionswithStakeholdersandUpperManagement1/2005–12/2006:Gradual Implementation1/2007:FullImplementationQbR:从提出到完善QbR的内涵Question-basedReviewisageneralframeworkforascienceandrisk-basedassessmentofproductqualityQuestion-basedReviewcontainstheimportantscientificandregulatoryreviewquestionsto关键制备工艺及其质控产品的工艺、处方是否有设计缺陷强调QbDQbR的内涵Question-basedReviewisANDAsUnderQbR(Continued)FutureGenericApplications

genericsponsorssubmitgenericapplicationsbasedontheformatofICHCTD,preferably,electronicallyModule1:AdministrativeInformationModule2:QualityOverallSummaryandClinicalSummaryModule3:QualityPharmaceuticalDevelopment;QualitybyDesignModule4:NonclinicalModule5:Clinical(Bioequivalence)ANDAsUnderQbR(Continued)Fut新药申报（NDA）

和仿制药申报（ANDA）的比较1.Chemistry2.Manufacturing3.Controls4.Labeling5.Testing6.AnimalStudies7.ClinicalStudies8.BioavailabilityNDArequirementsANDArequirements1.Chemistry2.Manufacturing3.Controls4.Labeling5.Testing6.Bioequivalence新药申报（NDA）和仿制药申报（ANDA）的比较1.Che美国仿制药申报模块1包含了管理和处方信息，这个是区域特异的。在美国应包括以下信息：①申请书3674；②专利认证信息；③原研药信息，包括NDA号、药名和生产商；④仿制药和原研药的对比，包括使用条件、有效成分、非有效成分、给药途径、剂型和剂量；⑤环境影响分析；⑥药品说明书（草稿）。

模块2模块2为概论。它包括药理作用分类，作用模式以及临床适应证。模块3应该包含原料药和制剂相关的化学、生产和质量控制信息。FDA仿制药部（OGD）鼓励申请人根据ICH对于人用药物的注册技术要求，即通用技术文件（CTD）的格式，提交ADNA。包括以下模块：美国仿制药申报模块1包含了管理和处方信息，这个是区域特异的。模块4模块4是关于动物实验的信息，并不是ANDA要求的。所以，仿制药申请一般不包含模块4。

模块5模块5是临床研究报告。对于ADNA，生物等效性信息应该在这个部分体现，包括：①生物等效性研究；②体外－体内相关性研究；③生物分析方法开发。案例报告，包括不良反应事件报告也应包括在此。

模块4模块4是关于动物实验的信息，并不是ANDA要求的。所以

OGDQBR

Thequestionbasedreview(QBR)servesasageneralframeworkfortheCMCassessmentofANDAsthatfocusesoncriticalpharmaceuticalattributesofproductquality.Withjustification,deviationsoralternateapproachestothisframeworkcanbeutilize,asnecessary,toensuretheadequacyoftheassessmentofproductquality

Foreaseofdiscussion,asimpledosageformisdefinedasasolutionoranimmediaterelease(IR)solidoraldosageform.OGDQBR

Theque42QBR:DrugSubstanceDescriptionandCharacterizationWhatarethenomenclature,molecularstructure,molecularformula,andmolecularweight?WhatarethepKa,aqueoussolubility(asfunctionofpH),partitioncoefficient,polymorphism,hygroscopicity,andmeltingpoints?ControlofDrugSubstanceAppearanceandIdentificationArethespecificationsforappearanceandidentificationappropriate?AssayIstheproposeddrugsubstanceassaylimitacceptable?Istheanalyticalmethodvalidatedandstability-indicating?ImpuritiesandResidualSolventsAreallthepossibleimpuritiesaccountedfor?Whatisthejustificationfortheimpurityacceptancelimits?Aretheanalyticalmethodsvalidatedandsuitablefortheirintendedfunction?AdditionalSpecificationsBasedonthereviewofthedrugproductandmanufacturingprocessarespecification(s)requiredonparticlesize,solidstateform,moisturecontent,orotherpropertiesofthedrugsubstanceandwhy?

Foreachadditionalspecification:Whatisthejustificationfortheacceptancelimit?Isitsuitableforitsintendedfunction?QBR:DrugSubstanceDescriptionQBR:DrugProductDescriptionandCompositionWhatarethecomponentsandcompositionofthefinalproduct?Whatisthefunctionofeachexcipient?DoanyexcipientsexceedIIGlimitsinthecontextofmaximumdailydoseandrouteofadministration?IfproductisanNTIdrugoranon-simpledosageformAretheresignificantdifferencesbetweenthisformulationandtheRLDthatpresentpotentialconcernswithrespecttoproductperformance?

ControlofExcipientsWhatarethespecificationsfortheinactiveingredientsandaretheyappropriatepertheirintendedfunction?SimpleDosageForm:EitherasolutionoranIRsolidoraldosageformQBR:DrugProductDescriptionaQBR:DrugProduct(Continued)ManufactureForallproductsDoesthebatchformulaaccuratelyreflectthedrugproductcomposition?Ifnot,whatarethedifferencesandthejustifications(e.g.potencyadjustment,overage,excesscoatingsolution,etc.)?Ifproductisnotasolution

Whatarethekeyunitoperationsinthedrugproductmanufacturingprocess?Arein-processtestsidentifiedbythesponsorappropriate?Whatisthedifferenceinsizebetweencommercialscaleandbiobatchanddotheyusethesameunitoperations?IfproductisanNTIdrugoranon-simpledosageformWhatarethecriticalstepsinthemanufacturingprocess?Whatarethein-processtests/controlsthatensureeachcriticalstepissuccessful?Intheproposedscaleupprocesswhatoperatingconditionswillbeadjustedtoensuretheproductmeetsallin-processandfinalproductspecifications?Whydoyoubelievethesponsorhasdemonstratedareasonableplantoscaleuptheprocess?QBR:DrugProduct(Continued)MQBR:DrugProduct(Continued)ControlofDrugProductIdentityIsthespecificationfortheidentityofthedrugproductappropriate?AssayandUniformityAretheproposeddrugassaylimitsacceptable?Istheassaymethodvalidatedandstability-indicating?Howisthecontentuniformityevaluated?Isitacceptable?Impurities/DegradationProductsArethedegradationproductsandtheiroriginsadequatelydescribed?Whatisthejustificationfortheacceptancelimitsondegradationproducts?Aretheanalyticalmethodsvalidatedandsuitablefortheirintendedfunction?Dissolution

Whatarethedissolutionmethodsandacceptancecriteriaandhowweretheyselected?Whatisthesignificantroleofdissolutiontestingforthisproduct?AdditionalSpecificationsArethereadditionalspecificationsthatarerequiredtoensuretheproductwillperformaslabeledandwhy?Foreachadditionalspecification:Whatisthejustificationfortheacceptancelimit?Aretheanalyticalmethodsvalidatedandsuitablefortheirintendedfunction?QBR:DrugProduct(Continued)CQBR:DrugProduct(Continued)ReferenceStandardArethereaqualificationreportandCOAprovidedforthereferencestandardoristhismaterialpurchasedfromanappropriatesource?Container/ClosureSystemHasthecontainer/closuresystembeenusedinapreviouslyapprovedproductorotherwisequalifiedforthisdosageform?Whatspecificcontainer/closureattributesarenecessarytoensureproductperformance?DrugProductStabilityDataWhatstabilitydatahasbeensubmitted?Hasthesponsorprovidedstabilitydataforthedrugproductpackagedintheproposedcontainer/closure?AcceptancelimitsAreallattributesthatcouldchangeovertimeevaluatedinthestabilitytests?Whataretheacceptablelimitsontheseattributes?

Shelf-liferecommendationWhatisthejustificationofshelflife?Isthepost-approvalstabilityprotocolacceptable?QBR:DrugProduct(Continued)RQBR:ProductDevelopmentReportforComplexDosageFormsandNTIDrugsDrugSubstanceWhichpropertiesorphysicalchemicalcharacteristicsofthedrugsubstanceaffectdrugproductperformance?ExcipientsIsthereanyevidenceofincompatibilitybetweentheexcipientsanddrugsubstance?FormulationWhatistheformulationintendedtodo?Whatmechanismdoesitusetoaccomplishthis?Wereanyotherformulationalternativesinvestigatedandhowdidtheseperform?Wereanyformulationoptimizationorsensitivitystudiescarriedoutforvariationsincompositionaroundthefinalformulation?Werethesestudiessufficienttoestablishadesignspaceforformulationcomposition?Istheformulationdesignconsistentwiththedosageformclassificationinthelabel?DrugProductWhatarethecriticalqualityattributesthatensuretheproductwillperformaslabeled?QBR:ProductDevelopmentReporQBR:ProcessDevelopmentReportProcessDescriptionWhywasthismanufacturingprocessselectedforthisdrugproduct?Werealternativeunitoperationsinvestigatedbyprocessdevelopmentstudies?CriticalStepsandScaleUpHowwerethecriticalstepsintheprocessidentified?Whatarethecriticalprocessparametersforeachcriticalstepandhowweretheyidentified,monitoredand/orcontrolled?Wereprocessdevelopmentstudiesthatvariedstartingmaterialsoroperatingparametersconducted?Werethesestudiessufficienttoestablishadesignspaceforprocess?InprocesstestsWhyiseachinprocesstestrequired?Howweretheacceptancelimitschosen?Whywerethein-processtestsidentifiedascriticaltoproductquality?Whatscale-upexperiencedoesthesponsorhavewiththeunitoperationsinthisprocess?QBR:ProcessDevelopmentReporQBR:RiskSummaryNTIdrugClassifiedasanon-NTIdrug,riskscore=+0ClassifiedasanNTIdrug,riskscore=+1DosageFormSimpleDosageForm,riskscore=+0OtherDosageFormsandNTIdrugs,riskscore=+1DevelopmentReportIfthesponsorsubmitsadevelopmentreportthataddressestheFDA’squestions:Riskscore=+0SolutionandIRProducts:ProductDevelopmentReportOtherDosageForms:ProductandProcessDevelopmentReportsInsufficientormissingdevelopmentreport,riskscore=+1IftheapplicationisofhighoverallqualityLessthanorequalto2cycles,riskscore=+0.Greaterthan2cycles,riskscore=+1QBR:RiskSummaryNTIdrugQBR:Risk-Based